In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter that is released by an afferent neuron and a surface receptor on a receiving neuron which causes excitation of the receiving neuron. L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway in mammals and is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors. The excitatory amino acids are of great physiological importance playing roles in a variety of physiological processes such as synaptic plasticity, motor control, respiration, cardiovascular regulation and sensory perception. Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed ionotropic. This type of receptor has been subdivided into at least three subtypes which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartic acid (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainic acid (KA). The second general type of receptor is the G-protein or second messenger-linked metabotropic excitatory amino acid receptor.
The metabotropic glutamate (mGlu) receptors belong to the super-family of G-protein coupled receptors and have been divided into three groups based on protein sequence homologies. Molecular cloning and functional expression studies in heterologous cell lines have shown that group I mGlu receptors: mGlu1 and mGlu5 and their spliced isoforms stimulate activation of phospholipase C (PLC) and mobilization of intracellular calcium whereas the group II (mGlu2 and 3) and III (mGlu4, 6,7 and 8) mGlu receptors negatively modulate adenyl cyclase. Stimulation of mGlu 5 (and mGlu1) receptors promotes an increase in neuronal excitation and fast synaptic transmission via potentiation of NMDA and AMPA receptor mediated responses, induction of Ca2+-depolarization by inhibition of several K+ channels, activation of dependent and Ca2+-independent non-selective cationic inward currents, enhancement of presynaptic glutamate release and enhancement of Na+/Ca2+ exchange. In addition to the activation of PLC, the signaling of group I mGlu receptors has also been shown to involve activation of other intracellular enzymes including phospholipase D, adenylate cyclase, tyrosine kinase and MAP kinases. In situ studies have shown that mGlu5 receptor splice variants (mGlu5a, b, c and d receptors) are localized peri- or extra-synaptically on the post synaptic membrane and are expressed in key neuroanatomical sites of the brain and spinal cord associated with psychiatric and neurological dysfunctions.
EP 0 436 398 B1 discloses acetylenes disubstituted with a heteroaromatic group and a substituted phenyl group having retinoid like activity.
WO 01/16121 discloses heterocyclic compounds and methods of use thereof.
U.S. Patent Publication No. 2003/0225070 A1 discloses phenylethynyl and styryl derivatives of imidazole and fused ring heterocycles.
WO 01/72709 A1 discloses naphthalene derivatives and their pharmaceutical use.
5-Phenylethynyl-nicotinonitrile is commercially available from Maybridge Chemical Co., Ltd.
Compounds of the present invention are useful as mGlu5 receptor antagonists and may have certain advantages over other mGlu5 receptor antagonists such as increased potency; enhanced mGlu5 selectivity vs. other CNS receptor and transporter targets; avoidance of undesirable activities, including reactive metabolite formation and inhibition of cytochrome p450 isozyme CYP1A2; superior mGlu5 receptor occupancy; or superior efficacy in rodent models of anxiety and depression. (Animal models for anxiety include, for example, the conditional emotional response model, Neuropharmacology, 13(1):1-9 (1974), J. Pharmacol. Exp. Ther., 254(2):420-426 (1990), Neurochem. Res., 17(5):497-507 (1992) or the Stress-Induced Hyperthermia model, Eur. J. Pharmacol., 294(1):125-135, Eur. J. Pharmacol., 435(2-3):161-170, Eur. J. Pharmacol., 463(1-3):117-132).
The compounds of the present invention have now been found to act as antagonists of mGlu5 receptors.